Field of the Invention
The present invention relates to particles comprising three active ingredients for administration by inhalation. In particular, the present invention relates to microparticles comprising a combination of an anticholinergic, a beta2-adrenoceptor agonist, and an inhaled corticosteroid, processes for the preparation of such particles, and the use of such particles for the prevention and/or treatment of respiratory diseases.
Discussion of the Background
Respiratory diseases are a common and important cause of illness and death around the world. In fact, many people are affected by inflammatory and/or obstructive lung diseases, a category characterized by inflamed and easily collapsible airways, obstruction to airflow, problems of exhaling and frequent medical clinic visits and hospitalizations. Types of inflammatory and/or obstructive lung disease include asthma, bronchiectasis, bronchitis and chronic obstructive pulmonary disease (COPD).
In particular, chronic obstructive pulmonary disease (COPD) is a multi-component disease characterized by airflow limitation and airway inflammation. Exacerbations of COPD have a considerable impact on the quality of life, daily activities and general well-being of patients and are a great burden on the health system. Thus, the aims of COPD management include not only relieving symptoms and preventing disease progression but also preventing and treating exacerbations.
While available therapies improve clinical symptoms and decrease airway inflammation, they do not unequivocally slow long-term progression or address all disease components. With the burden of COPD continuing to increase, research into new and improved treatment strategies to optimize pharmacotherapy is ongoing.
Currently, there are several recommended classes of therapy for COPD, of which bronchodilators such as β2-agonists and anticholinergics are the mainstay of symptom management in mild and moderate disease, prescribed on an as-needed basis for mild COPD and as a maintenance therapy for moderate COPD.
Said bronchodilators are efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
For the treatment of more severe COPD, guidelines recommend the addition of inhaled corticosteroids (ICSs) to long-acting bronchodilator therapy. Combinations of therapies have been investigated with a view to their complementary modes of action enabling multiple components of the disease to be addressed. Data from recent clinical trials indicate that triple therapy, combining an anticholinergic with an ICS and a long-acting β2-agonist (LABA), may provide additional clinical benefits to those associated with each treatment alone in patients with moderate to severe COPD.
Furthermore, there is evidence suggesting synergistic actions of the LABA and ICS as long as both active ingredients are present at the same site of action, for example the small peripheral airways of the pulmonary tree. Without being limited by the theory, this might also occur if the anti-muscarinic drug is delivered at said site of action.
An interesting triple combination, presently under investigation, includes:
(i) formoterol, particularly its dihydrate fumarate salt (hereinafter indicated as FF), a long acting beta-2 adrenergic receptor agonist, currently used clinically in the treatment of bronchial asthma, COPD and related disorders;
(ii) rac-glycopyrronium bromide (hereinafter indicated as GB), an antimuscarinic drug recently approved for the maintenance treatment of COPD; and
(iii) beclometasone dipropionate (hereinafter indicated as BDP) a potent anti-inflammatory corticosteroid, available under a wide number of brands for the prophylaxis and/or treatment of asthma and other respiratory disorders.
On the other hand, current combined inhalation products may be subjected to a great variability in the dose delivery of each active ingredient, which in turn may be perpetuated as a function of product storage conditions.
Hence, it would be advantageous to provide combination-particles for inhalation, and a process of preparation thereof, that will allow all the three active ingredients to be delivered without significant dose variations.
Furthermore, there is still a need of an improved therapeutic control of patients exhibiting respiratory diseases affecting the small peripheral airways.
Therefore, it would highly be advantageous to provide combination-particles, and a process of preparation thereof, whereby all the three active ingredients could simultaneously reach the distal tract of the respiratory tree, and hence improving small airways outcomes and associated control.
In the prior art, different approaches have been proposed for preparing particles incorporating a combination of two or more active ingredients. For example, WO 02/28377, WO 2010/097188, and WO 2013/021199, all of which are incorporated herein by reference in their entireties, disclose particles incorporating, inter alia, a LABA and an ICS. However, none of said documents disclose particles incorporating a combination of formoterol salts, beclometasone dipropionate and glycopyrronium salts. Furthermore, they are all silent about the problem of reaching the distal tract of the respiratory tree.